Foremost among the animal models of human insulin-dependent diabetes mellitus is the BB rat. These animals abruptly become ketoacidotic, experience complete destruction of pancreatic beta cells, and requier exogenous insulin administration for survival. A number of studies suggest that this model of diabetes has an autoimmune pathogenesis. To test the hypothesis that spontaneous diabetes in the BB rat results from a failure of autoregulation within the immune system, we plan to conduct experiments designed either to induce or prevent diabetes. We plan first to isolate and to identify the cell or cells that destroy pancreatic beta cells in this animal. In addition, the cellular mechanism by which this destruction takes place will be studied. We will attempt to purify and characterize the soluble cellular products that mediate beta cell destruction. The microenvironmental factors and specific characteristics of the target beta cells of BB rats that render this animal susceptible to diabetes will also be examined. In experiments complementary to those designed to elucidate the mechanism of induction, we will attempt to identify the various cell(s) and/or cellular products responsible for prevention of diabetes in this animal. Advanced technology diffusion chambers will play an important role in these studies. We also intend to study BB islet physiology in vitro. We will use the method of isolated perfusion of the pancreas to quantitate insulin secretion. With this mehtod we can trace important pathophysiological events as they ocur during the development of spontaneous diabetes. Additionally, we will be able to perfuse the isolated pancreas with cells and cell products involved in the induction of diabetes. Our long range goal is to achieve the ability to induce and prevent diabetes in a predictable manner in the BB rat. These experiments should allow us to assess the validity of the original hypothesis that insulin dependent diabetes mellitus results from an immunoregulatory defect.